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Hypoxic cardiomyocyte-derived exosomes regulate cardiac fibroblast activation, apoptosis, migration and ferroptosis
1Department of Cardiology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China.
Insights
Hypoxic cardiomyocyte-derived exosomes carrying miR-208a/b promote cardiac fibroblast (CF) viability, migration, and collagen production. These exosomes also influence ferroptosis, highlighting a novel communication pathway in myocardial disease.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Cardiomyocytes and cardiac fibroblasts (CFs) interact via exosomes, influencing myocardial function.
- Exosomes from myocardial diseases often contain elevated miR-208a/b, microRNAs specific to the heart.
- The precise mechanisms of exosome-mediated intercellular communication in cardiac conditions remain under investigation.
Purpose of the Study:
- To investigate the role of miR-208a/b in exosomes derived from hypoxic cardiomyocytes (H-Exo).
- To elucidate the effects of H-Exo on cardiac fibroblast biological functions, including viability, migration, and extracellular matrix production.
- To determine the impact of H-Exo on ferroptosis in cardiac fibroblasts.
Main Methods:
- Cardiomyocytes were subjected to hypoxia to induce exosome secretion (H-Exo).
- H-Exo were co-cultured with cardiac fibroblasts (CFs) to assess exosome uptake and functional changes.
- miR-208a/b inhibitors were used to block specific microRNA functions.
- Cell viability, migration assays, α-SMA, collagen I/III expression, apoptosis, caspase-3 activity, and ferroptosis markers (ROS, MDA, Fe2+, GPX4) were analyzed.
Main Results:
- CFs internalized H-Exo, leading to increased miR-208a/b expression.
- H-Exo significantly enhanced CF viability, migration, α-SMA, collagen I/III expression, and secretion.
- Inhibition of miR-208a/b attenuated H-Exo-induced effects on CFs and reversed H-Exo's anti-apoptotic action.
- H-Exo exacerbated ferroptosis in CFs, indicated by increased ROS, MDA, Fe2+, and decreased GPX4, an effect partially reversed by miR-208a/b inhibitors.
Conclusions:
- Hypoxic cardiomyocyte-derived exosomes regulate cardiac fibroblast biological functions via miR-208a/b.
- miR-208a/b within H-Exo promote fibroblast activation and collagen production.
- H-Exo influences cardiac fibroblast ferroptosis, suggesting a role in myocardial remodeling and disease progression.
Abstract:
Studies have found that cardiomyocytes and cardiac fibroblasts (CFs) can communicate through exosomes, thereby affecting each other's biological functions, but there are few studies on the mechanism. miR-208a/b are specifically expressed in the heart and highly expressed in exosomes derived from various myocardial diseases. Hypoxia induced cardiomyocytes to secrete exosomes (H-Exo) with high expression of miR-208a/b. When H-Exo were added to CFs for co-culture, it was found that CFs took up exosomes, thereby upregulating the expression of miR-208a/b. H-Exo significantly promoted the viability and migration of CFs, enhanced the expression of α-SMA, collagen I and III, and promoted the secretion of collagen I and III. miR-208a or/and miR-208b inhibitors significantly attenuated the effects of H-Exo on CF biological functions. miR-208a/b inhibitors significantly enhanced the levels of apoptosis and caspase-3 activity in CFs, while H-Exo significantly attenuated the pro-apoptotic effects of miR-208a/b inhibitors. Further treatment of CFs with ferroptosis inducer Erastin found that H-Exo further enhanced the accumulation of ROS, MDA and Fe2+, the main indicators of ferroptosis, and inhibited the expression of GPX4, a key regulator of ferroptosis. miR-208a or/and miR-208b inhibitors significantly attenuated the effects of Erastin and H-Exo on ferroptosis. In conclusion, hypoxic cardiomyocyte-derived exosomes can regulate the biological functions of CFs through highly expressed miR-208a/b.
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